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. 2016 Nov 7;13(11):3835-3841.
doi: 10.1021/acs.molpharmaceut.6b00633. Epub 2016 Oct 15.

Light Control of Insulin Release and Blood Glucose Using an Injectable Photoactivated Depot

Bhagyesh R Sarode  1 , Karen Kover  2   3 , Pei Y Tong  2 , Chaoying Zhang  2 , Simon H Friedman  1
Affiliations

Light Control of Insulin Release and Blood Glucose Using an Injectable Photoactivated Depot

Bhagyesh R Sarode et al. Mol Pharm. .

Abstract

In this work we demonstrate that blood glucose can be controlled remotely through light stimulated release of insulin from an injected cutaneous depot. Human insulin was tethered to an insoluble but injectable polymer via a linker, which was based on the light cleavable di-methoxy nitrophenyl ethyl (DMNPE) group. This material was injected into the skin of streptozotocin-treated diabetic rats. We observed insulin being released into the bloodstream after a 2 min trans-cutaneous irradiation of this site by a compact LED light source. Control animals treated with the same material, but in which light was blocked from the site, showed no release of insulin into the bloodstream. We also demonstrate that additional pulses of light from the light source result in additional pulses of insulin being absorbed into circulation. A significant reduction in blood glucose was then observed. Together, these results demonstrate the feasibility of using light to allow for the continuously variable control of insulin release. This in turn has the potential to allow for the tight control of blood glucose without the invasiveness of insulin pumps and cannulas.

Keywords: DMNPE; insulin; light controlled drug release; photoactivated depot.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
PhotoActivated Depot (PAD) approach. PAD material consisting of insulin linked to polymer via photocleavable linker injected under the skin. This is followed by transcutaneous irradiation, photolysis of the insulin–PAD bond, and uptake into circulation.
Figure 2
Figure 2
Synthesis of PAD material using a 10 μm Rink-amide Tentagel resin coupled with strained cyclo-octyne, then reacted with IMA (insulin monoazide) containing one photocleavable group. Final material photolyzes to release native insulin.
Figure 3
Figure 3
In vitro insulin PAD photolysis. PAD material was exposed to two 2′ periods of 365 nm LED light (blue bars). Supernatant was monitored for insulin release (left). Material released showed a retention time in HPLC consistent with insulin (upper right), and this was confirmed to be insulin via ESI-MS (lower right).
Figure 4
Figure 4
Confirmation of in vivo activity of in vitro photolyzed insulin from the PAD. Insulin isolated from photolyzed PAD material was injected into the dermal layer of diabetic rats (n = 3). Insulin (blue circles) was rapidly detected in the blood. Blood glucose (purple squares) was reduced, confirming in vivo activity of in vitro photolyzed PAD insulin.
Figure 5
Figure 5
Compact LED light source used for in vivo studies. Light source shown from top and bottom (left and middle panels) and in place on rat back (right panel).
Figure 6
Figure 6
Photoactivated insulin release. Blood insulin levels, as determined by ELISA assay (top panel), and blood glucose levels (bottom panel) before and after a 2 min period of LED activation (indicated by blue bar). * indicates p < 0.05 for differences between control and experimental points.
Figure 7
Figure 7
Insulin release and blood glucose reduction with multiple irradiations of PAD. Blood insulin levels, as determined by ELISA assay (top panel), and blood glucose levels (bottom panel) before and after 2 min periods of LED activation at time 0 and 65 min (indicated by blue bar). * indicates p < 0.05 for differences between control and experimental points.
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